Division of Genetics and Developmental Medicine

Phillip F. Chance, MD, is currently Chief, Division of Genetics and Developmental Medicine in the Department of Pediatrics at the University of Washington School of Medicine. He has joint appointment as Professor of Neurology in the Department of Neurology, and also holds the Allan and Phyllis Treuer Endowed Chair in Genetics and Development at Children's Hospital and Regional Medical Center in Seattle.

Dr. Chance is the Director of the Neurogenetics Laboratory in the Department of Pediatrics. His laboratory conducts research in four main areas: juvenile Lou Gehrig's Disease (amytrophic lateral sclerosis or ALS4), Charcot-Marie-Tooth neuropathy, hereditary neuralgic amyotrophy (HNA) and Joubert sydrome and related cerebellar malformations.

Amytrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disorder associated with sever loss of motor neurons in the brain, brainstem, and spinal cord. ALS typically has a rapid course and leads to death within 3 to 5 years after the onset of clinical symptoms. While ALS of any type is almost exclusively seen in adults, there are "juvenile" forms (which have onset in childhood or adolescence) that manifest a chronic, slowly progressing course. We have identified a region on chromosome 9q34, which harbors the gene of an autosomal dominant form of juvenile ALS. Current work to identify and characterize the gene for ALS mapping to chromosome 9q34 has included characterizing the gene and protein and developing a mouse model.

Charcot-Marie-Tooth neuropathy is a group of inherited disorders characterized by degenerative changes in peripheral motor and sensory nerves. We have identified six mutations in the SIMPLE gene as the cause of CMT1C, an autosomal dominant, childhood onset, demyelinating neuropathy. It is not know if CMT1C results from haplo-insufficiency, dominant-negative or a gain-of-function mechanism. Our goal is to gain insight into the pathway in which SIMPLE operates in Schwann cells (SC) and into the disease mechanism in CMT1C where SC appear to the primary site of pathology. Insights gained from this study will have direct benefits for the field of peripheral neuropathy research and diagnosis and may have greater implications for other demyelinating disorders such as multiple sclerosis.

Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal dominant disorder associated with recurrent painful brachial plexus dysfunction. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attacks. The biochemical and molecular basis of HNA is unknown. The gene for HNA has been finely mapped to chromosome 17q25 with few pedigrees showing genetic heterogeneity. Identification of the HNA gene will permit the assessment of its patterns of tissue distribution and developmental expression in addition to providing novel insights into the molecular and biochemical abnormalities leading to both the HNA phenotype. Moreover, characterization of the HNA gene may have broader pathophysiological and therapeutic implications for more common idiopathic forms of brachial neuropathy.

Joubert syndrome (JS) is a rare autosomal recessive malformation syndrome involving agenesis of the cerebellar vermis with accompanying brainstem malformations. JS is clinically characterized by the core features of hypotonia, developmental delays, abnormal respiratory patterns, and abnormal eye movement, it exhibits variable additional clinical features, and confusion exists regarding its precise definition. Genetic locus heterogeneity is likely, and genes crucial to cerebellar and brainstem development are functional JS candidates, particularly homeotic genes specifying the vermian domain. This project involves collecting medical records and blood samples for DNA isolation from multiple families with JS and carrying out a genome-wide scan for regions of haplotype sharing in pedigrees with consanguinity. From this data, the goal is to discover mutations leading to JS in specific functional and positional candidate genes.

HNA Article- News-Medical.Net